Periodic Reporting for period 1 - FI4P (Flow and Iron for Pharma)
Reporting period: 2020-03-16 to 2022-03-15
Synthetic chemistry must provide more and more sustainable methods to build the chemical structures needed from materials to life sciences. Transition metal catalysed cross-couplings have become a versatile tool for the organic chemist, and in this context we focused on using iron, a metal with low toxicity, high abundance and sometimes unique reactivity. To control the reactivity of the organometallic building blocks used in these cross-coupling reactions, we decided to leverage the advantages of continuous flow chemistry. Flow technology goes beyond transposing batch chemistry to flow reactors: it can enable unique process conditions and allow precise spatiotemporal control, while reducing the energy required to run processes thanks to efficient heat transfer properties.
Over the course of the Action, an extensive optimisation of reaction conditions was carried out, with the aim to develop protocols of interest to the discovery and manufacture of pharmaceuticals. Due to results of limited synthetic utility, we decided to work on improving our discovery process and implement an automated flow chemistry platform. This allowed us to streamline optimisation protocols, improve experimental reproducibility and reduce exposure to hazardous chemicals. The interest of our in-house automated platform has been validated during the Action, and we expect its continued use for the development of further reaction conditions in our laboratory will eventually inspire others to adopt automation technology in synthetic chemistry.
Over the course of the Action, an extensive optimisation of reaction conditions was carried out, with the aim to develop protocols of interest to the discovery and manufacture of pharmaceuticals. Due to results of limited synthetic utility, we decided to work on improving our discovery process and implement an automated flow chemistry platform. This allowed us to streamline optimisation protocols, improve experimental reproducibility and reduce exposure to hazardous chemicals. The interest of our in-house automated platform has been validated during the Action, and we expect its continued use for the development of further reaction conditions in our laboratory will eventually inspire others to adopt automation technology in synthetic chemistry.
Continuous-flow chemical protocols were developed for the generation of reactive intermediates including organolithiums, organomagnesiums and alkyl triflates and their use in cross-coupling reactions. To improve the efficiency of those protocols, an in-house automated flow chemistry platform was developed. This platform aims to autonomously select reagent, control experimental conditions (temperature, flow rates, concentrations) and collect samples, in compliance with safety protocols. Various modules were designed and built, including valves, collectors, reactors, and sensors. A control program was developed, allowing the chemist to program a sequence of test reactions and remotely monitor its execution. The platform also allows the rapid diversification of chemical structures, with the ability to combine sets of substrates and generate libraries of compounds.
Following the Action’s, new chemical processes will be published allowing the preparation of chemical matter of interest to the pharmaceutical industry, under more environmental-friendly conditions than standard protocols. In addition, the automated flow chemistry platform will build on stand-alone, in-house tools previously reported in the literature. This will provide any synthetic chemistry laboratory with an interest in flow technology with an opportunity to start using the possibilities granted by automation in chemical research, including increased productivity, higher repeatability of experiments, and safer handling of hazardous chemicals and conditions.